The kinase inhibitors Sunitinib and Sorafenib differentially affect reactivity of NK cells against Renal Cell Cancer

Abstract

Sunitinib and Sorafenib are multi‐kinase inhibitors licensed for the treatment of patients with advanced renal cell cancer (RCC) and target, among others, VEGF receptors, PDGF receptors, c‐kit and Flt3. Beyond that, Sorafenib inhibits c‐RAF and B‐RAF. Here we report that Sorafenib but not Sunitinib significantly (p<0.05, Mann‐Whitney U‐test) reduce cell surface CD107a expression (about 50%) on NK cells as a surrogate marker for degranulation in response to tumor targets. In line, pharmacological levels of Sorafenib but not Sunitinib significantly (p<0.05) diminish cytotoxicity of primary NK cells against the RCC cell lines A498, ACHN and CAKI‐2 (46% to 14%, 52% to 22% and 63% to 42%, respectively) in chromium release assays. While Sunitinib had no effect, Sorafenib, alike the specific c‐RAF inhibitor ZM336372 or the specific MEK inhibitor PD98059, markedly reduces ERK phosphorylation which regulates the movement of lytic granula towards target cells. Our results indicate that NK cell anti‐tumor reactivity is impaired by Sorafenib but not by Sunitinib due to the additional inhibitory effect of Sorafenib on the ERK pathway, which has been demonstrated to dictate NK cell cytotoxicity. We therefore conclude that Sunitinib is exquisitely suitable for combination with immunotherapeutic approaches in RCC patients.